The goal of this project is to develop a rat model of fibromyalgia pain which could provide the basis for future research into this complex disease. The difficulty in finding an etiology for this painful condition is in part because fibromyalgia is not a discrete or unique disease, but patients also a display number of different symptoms in addition to the widespread tenderness, including fatigue, sleep disturbances, headaches, gastrointestinal symptoms, etc. As such, fibromyalgia overlaps conditions such as Chronic Fatigue Syndrome, Irritable Bowel Syndrome, tension and migraine headaches. These conditions share several features, including a female predominance, initiation or exacerbation in response to several different types of "stressors", and response to similar types of pharmacologic and non-pharmacologic modalities (e.g. tricyclic drugs, aerobic exercise). A dysfunction of the noradrenergic system, the basis for the proposed model, presents a unifying explanation for many seemingly disparate findings in fibromyalgia by accounting for the neuroendocrine and autonomic abnormalities, in addition to the chronic pain. Our guiding hypothesis is that in fibromyalgia, chronically decreased noradrenergic input to the spinal cord facilitates substance P release and subsequent hyperalgesia (decreased threshold for pain). This hypothesis is based on both clinical evidence of decreased noradrenaline and increased substance P in the spinal cord of fibromyalgia patients, as well as evidence from basic research demonstrating that acute decreases in spinal noradrenaline allow for greater release of substance P and sustained hyperalgesic effects of this neurotransmitter. These alterations in turn result in greater expression and redistribution of the substance P receptor in the spinal cord, contributing to the chronicity of the hyperalgesia. In the female rat, we will apply a novel technique of selective immunolesion of brainstem noradrenergic input to nociceptive areas of the spinal cord. The first aim will test the hypothesis that lowered nociceptive thresholds in rats with decreased spinal noradrenaline depend on substance P neurotransmission. This hypothesis will be tested by determining the contribution of spinal SP neurotransmission in alterations of nociceptive behavioral and neuronal responses to noxious and innocuous stimuli. The second aim will test the hypothesis that chronically decreased spinal noradrenaline chronically increases basal levels, and facilitates evoked release of substance P, by measuring levels of substance P in the CSF, primary afferent neurons, and spinal cord, both basal and following noxious and innocuous stimulation. In the third aim, we will test the hypothesis that decreased spinal noradrenaline facilitates stimulus-induced increased expression and redistribution of the substance P receptor (NK1 receptor) in the spinal cord by measuring basal and noxious stimulus-induced alterations in the expression of this receptor.